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As a Tumor Suppressor: a Mechanistic Perspective

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As a Tumor Suppressor: a Mechanistic Perspective Review Transducer of ERBB2.1 (TOB1) as a Tumor Suppressor: A Mechanistic Perspective Hun Seok Lee 1,†, Juthika Kundu 1,†, Ryong Nam Kim 1,2 and Young Kee Shin 1,2,3,* Received: 10 September 2015; Accepted: 8 December 2015; Published: 15 December 2015 Academic Editor: Anthony Lemarié 1 Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Korea; [email protected] (H.S.L.); [email protected] (J.K.); [email protected] (R.N.K.) 2 Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul 08826, Korea 3 The Center for Anti-cancer Companion Diagnostics, School of Biological Science, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul 08826, Korea * Correspondence: [email protected]; Tel.: +82-2-880-9126; Fax: +82-2-883-9126 † These authors contributed equally to this work. Abstract: Transducer of ERBB2.1 (TOB1) is a tumor-suppressor protein, which functions as a negative regulator of the receptor tyrosine-kinase ERBB2. As most of the other tumor suppressor proteins, TOB1 is inactivated in many human cancers. Homozygous deletion of TOB1 in mice is reported to be responsible for cancer development in the lung, liver, and lymph node, whereas the ectopic overexpression of TOB1 shows anti-proliferation, and a decrease in the migration and invasion abilities on cancer cells. Biochemical studies revealed that the anti-proliferative activity of TOB1 involves mRNA deadenylation and is associated with the reduction of both cyclin D1 and cyclin-dependent kinase (CDK) expressions and the induction of CDK inhibitors. Moreover, TOB1 interacts with an oncogenic signaling mediator, β-catenin, and inhibits β-catenin-regulated gene transcription. TOB1 antagonizes the v-akt murine thymoma viral oncogene (AKT) signaling and induces cancer cell apoptosis by activating BCL2-associated X (BAX) protein and inhibiting the BCL-2 and BCL-XL expressions. The tumor-specific overexpression of TOB1 results in the activation of other tumor suppressor proteins, such as mothers against decapentaplegic homolog 4 (SMAD4) and phosphatase and tensin homolog-10 (PTEN), and blocks tumor progression. TOB1-overexpressing cancer cells have limited potential of growing as xenograft tumors in nude mice upon subcutaneous implantation. This review addresses the molecular basis of TOB1 tumor suppressor function with special emphasis on its regulation of intracellular signaling pathways. Keywords: anti-proliferative; apoptosis; invasion; migration; transducer of erbb2.1; tumor suppressor 1. Introduction The protein encoded by the transducer of ERBB2.1 (TOB1) is a member of the TOB/B cell translocation gene (BTG) family, which also consists of BTG1, BTG2/TIS21/PC3, BTG3, BTG4/PC3B, and TOB2 [1]. These family proteins are characterized by a N-terminal TOB/BTG homology domain which contains two short elements, Box-A (harboring Nuclear localization sequence (NLS)) and Box-B, which are a highly conserved and a non-conserved spacer sequence inserted between the two conserved A and B boxes [2] (Figure1). According to a recent report, the conserved N-terminal domain is a module for protein-protein interaction involved in binding to the paralogues CNOT7 (human Caf1/Caf1a) and CNOT8 (human Pop2/Calif/Caf1b), the deadenylase components of the CCR4-NOT complex, whereas the C-terminal region is less conserved and mediates unique protein-protein interactions specific to each family member. Structural analysis of the BTG domain Int. J. Mol. Sci. 2015, 16, 29815–29828; doi:10.3390/ijms161226203 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2015, 16, 29815–29828 implies the existence of a high degree of similarity between TOB1 and TOB2, and between BTG1 and BTG2, whereas BTG3 and BTG4 are less related to its members [3]. Among TOB/BTG protein family members, TOB1 and TOB2 have the longest C-terminal domains, involved in protein-protein interactions, which plays a pivotal role for transcription, mRNA turnover, and other regulatory functions.Int. BecauseJ. Mol. Sci. 2015 of, their16, page–page well-defined role in the inhibition of cell proliferation, TOB/BTG proteins are also known as anti-proliferative (APRO) family proteins [4]. In 1991, Bradbury et al. reported the firstwhereas member BTG3 of theand TOB/BTGBTG4 are less family, related which to its members was isolated [3]. Among from ratTOB/BTG pheochromocytoma protein family cells and namedmembers, PC3 (pheochromocytomaTOB1 and TOB2 have cell-3)the longest [5]. C-terminal In the same domains, year, Fletcherinvolved etin al.protein-proteinreported a mouse interactions, which plays a pivotal role for transcription, mRNA turnover, and other regulatory Pc3 homolog from 12-O-tetradecanoyl phorbol-13-acetate (TPA)-stimulated mouse NIH3T3 cells functions. Because of their well-defined role in the inhibition of cell proliferation, TOB/BTG proteins and namedare also it TPA-inducedknown as anti-proliferative sequence (APRO) 21 (Tis21 family)[6]. proteins In the [4]. following In 1991, Bradbury year, a et successful al. reported molecularthe cloningfirst of Bmember cell translocation of the TOB/BTG gene-1 family, (BTG1 which) fromwas isolated B cell from lymphocytic rat pheochromocytoma leukemia,presenting cells and 65% homologynamed with PC3Tis21 (pheochromocytoma/PC3, was reported cell-3) [[5].7]. In Later the same on, year, Rouault Fletcheret al. et al.cloned reportedBTG2 a mouseas the Pc3 human homologhomolog of the fromPC3 12-/Tis21O-tetradecanoylgene [8]. phorbol-13-acetate In the same year,(TPA)-stimulated Matsuda andmouse colleagues NIH3T3 cells reported and the cloningnamed of a cDNA it TPA-induced encoding sequence a novel 21 ( proteinTis21) [6]. termed In the following TOB1, year, which a successful exhibited molecular sequence cloning homology of B cell translocation gene-1 (BTG1) from B cell lymphocytic leukemia, presenting 65% homology to knownwith anti-proliferative Tis21/PC3, was reported gene [7]. product Later on, BTG-1 Rouault in itset al. nearly cloned halfBTG2 N-terminal. as the human Sequencinghomolog of the analysis of the nucleotidePC3/Tis21 gene revealed [8]. In thatthe same TOB1 year, is aMatsuda 45 kDa and protein colleagues that reported lacks a the Src cloning Homology of a cDNA 2 (SH2) or SH3 domain.encoding Whilea novel the protein N-terminal termed TOB1, half ofwhich TOB1 exhibited showed sequence sequence homology similarity to known with anti- BTG1, the C-terminalproliferative half is elucidatedgene product toBTG-1 have in its a uniquenearly half proline N-terminal. and Sequencing glutamine analysis [9]. This of the family nucleotide has about 20 membersrevealed which that haveTOB1 beenis a 45 discoveredkDa protein that from lacks different a Src Homology species, 2 ranging (SH2) or fromSH3 domain. nematodes While tothe human, N-terminal half of TOB1 showed sequence similarity with BTG1, the C-terminal half is elucidated to all retaining phylogenetically conserved homology [10]. The TOB1 transcripts are expressed in adult have a unique proline and glutamine [9]. This family has about 20 members which have been brain tissues,discovered in which from different they could species, play ranging pivotal from rolesnematodes in learning to human, and all retaining memory phylogenetically [11]. Similar to the TOB1, BTG2conservedmRNAs homology are [10]. elevated The TOB1 in thetranscripts ventricular are expressed zone ofin adult the central brain tissues, nervous in which system they (CNS), includingcould the play brain pivotal [12 roles]. Additionally, in learning and BTG2memory inhibits [11]. Similar medulloblastoma, to the TOB1, BTG2 amRNAs very aggressiveare elevated tumor of the cerebellum,in the ventricular by inhibiting zone of the proliferation central nervous and syst triggeringem (CNS), including the differentiation the brain [12]. of Additionally, the precursors of cerebellarBTG2 granule inhibits neurons medulloblastoma, [13]. The a veryTOB1 aggressivegene istumor mapped of the cerebellum, on chromosome by inhibiting 17q, proliferation which harbors a and triggering the differentiation of the precursors of cerebellar granule neurons [13]. The TOB1 gene series of tumor suppressor genes. The inactivation of tumor suppressor genes located on chromosome is mapped on chromosome 17q, which harbors a series of tumor suppressor genes. The inactivation 17 is associatedof tumor suppressor with stomach genes andlocated lung on chromosome cancer. In 17 a pioneeringis associated with study, stomach Yoshida and lung and cancer. colleagues In [14] first reporteda pioneering that TOBstudy,gene Yoshida knockout and colleagues mice show[14] first spontaneous reported that tumor TOB gene formations knockout mice primarily show in the lung, liver,spontaneous and lymph tumor nodes. formations Others primarily reported in the that lung TOB1, liver, restoration and lymph nodes. inhibits Others growth reported factor that receptor ERBB2-mediatedTOB1 restoration signaling inhibits [9 growth] and factor attenuates receptor tumor ERBB2-mediated cell survival signaling [15 [9]]. and Accumulating attenuates tumor evidence suggestscell that survival TOB1 functions[15]. Accumulating as a tumor evidence suppressor suggests protein. that TOB1 The functions purpose ofas thisa tumor review suppressor is to delineate protein. The purpose of this review is to delineate the molecular mechanisms underlying TOB1 tumor the molecularsuppressor mechanisms functions. underlying TOB1 tumor suppressor functions. Figure 1. Structural
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